A computer model of human atria with reasonable computation loadand realistic anatomical properties

Atrial fibrillation is the most frequent arrhythmia, provoking discomfort, heart failure and arterial embolisms. The aim of this work is to develop a simplified anatomical computer model of human atria for the study of atrial arrhythmias and the understanding of electrical propagation mechanisms. With the model we propose, up to 40 s of real-time propagation have been simulated on a single-processor computer. The size and the electrophysiological properties of the simulated atria are within realistic values and information about anatomy has been taken into account in a three-dimensional structure. Besides normal sinus beat, pathological phenomena such as flutter and fibrillation have been induced using a programmed stimulation protocol. One important observation in our model is that atrial arrhythmias are a combination of functional and anatomical reentries and that the geometry plays an important role. This virtual atrium can reproduce electrophysiological observations made in humans but with the advantage of showing in great detail how arrhythmias are initiated and sustained. Such details are difficult or impossible to study in humans. This model will serve us as a tool to evaluate the impact of new therapeutic strategies and to improve them.     

Preliminary analysis of COVID-19 academic information patterns: a call for open science in the times of closed borders

Scientometrics - The Pandemic of COVID-19, an infectious disease caused by SARS-CoV-2 motivated the scientific community to work together in order to gather, organize, process and distribute data...     

A numerical scheme for modeling wavefront propagation on a monolayer of arbitrary geometry

The majority of models of wavefront propagation in cardiac tissue have assumed relatively simple geometries. Extensions to complicated three-dimensional (3-D) representations are computationally challenging due to issues related both to problem size and to the correct implementation of flux conservation. In this paper, we present a generalized finite difference scheme (GDFS) to simulate the reaction-diffusion system on a 3-D monolayer of arbitrary shape. GDFS is a vertex-centered variant of the finite-volume method that ensures local flux conservation. Owing to an effectively lower dimensionality, the overall computation time is reduced compared to full 3-D models at the same spatial resolution. We present the theoretical background to compute both the wavefront conduction and local electrograms using a matrix formulation. The same matrix is used for both these quantities. We then give some results of simulation for simple monolayers and complex monolayers resembling a human atria.     

A Novel Cell-Based Model for a Rare Disease: The Tks4-KO Human Embryonic Stem Cell Line as a Frank-Ter Haar Syndrome Model System

Tyrosine kinase substrate with four SH3 domains (Tks4) scaffold protein plays roles in cell migration and podosome formation and regulates systemic mechanisms such as adult bone homeostasis and adipogenesis. Mutations in the Tks4 gene (SH3PXD2b) cause a rare developmental disorder called Frank-Ter Haar syndrome (FTHS), which leads to heart abnormalities, bone tissue defects, and reduced adiposity. We aimed to produce a human stem cell-based in vitro FTHS model system to study the effects of the loss of the Tks4 protein in different cell lineages and the accompanying effects on the cell signalome. To this end, we used CRISPR/Cas9 (clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated (Cas9)) to knock out the SH3PXD2b gene in the HUES9 human embryonic stem cell line (hESC), and we obtained stable homo- and heterozygous knock out clones for use in studying the potential regulatory roles of Tks4 protein in embryonic stem cell biology. Based on pluripotency marker measurements and spontaneous differentiation capacity assays, we concluded that the newly generated Tks4-KO HUES9 cells retained their embryonic stem cell characteristics. We propose that the Tks4-KO HUES9 cells could serve as a tool for further cell differentiation studies to investigate the involvement of Tks4 in the complex disorder FTHS. Moreover, we successfully differentiated all of the clones into mesenchymal stem cells (MSCs). The derived MSC cultures showed mesenchymal morphology and expressed MSC markers, although the expression levels of mesodermal and osteogenic marker genes were reduced, and several EMT (epithelial mesenchymal transition)-related features were altered in the Tks4-KO MSCs. Our results suggest that the loss of Tks4 leads to FTHS by altering cell lineage differentiation and cell maturation processes, rather than by regulating embryonic stem cell potential.     

Cooling of a sphere by natural convection – The applicability of the lumped capacitance method

Two approaches to predicting the sphere cooling process by laminar natural convection were compared in terms of the accuracy of the volume averaged sphere temperature and the heat transfer rate between the sphere and the surrounding fluid. The first approach is based on the formulation of conjugate heat transfer (heat conduction in the sphere and laminar natural convection in the fluid). The second approach includes the lumped capacity method based on the assumption that the temperature in the sphere is spatially uniform and on the Churchill correlation function. The solution to the problem depends on the Rayleigh number (Ra), the Biot number (Bi), the Prandtl number (Pr), and the sphere-to-fluid thermal diffusivity ratio (A). The lumped capacitance method gives fairly accurate results with respect to the conjugate heat transfer method (discrepancy in the volume averaged sphere temperature less than 5%) when A · Bi/Ra^0.452 < 0.05, for Bi < 0.15 and Pr > 1.     

Observer of autonomic cardiac outflow based on blind source separation of ECG parameters

We present a novel method which provides an observer of the autonomic cardiac outflow using heartbeat intervals (RR) and QT intervals. The model of the observer is inferred from qualitative physiological knowledge. It consists in a problem of blind source separation of noisy mixtures which is resolved by a simple and robust algorithm. The robustness of the algorithm has been assessed by numerical simulations in adverse noisy environments. In clinical applications, we have validated the observer on subjects exposed to experimental conditions known to elicit sympathetic or parasympathetic response.     

Characterization of the Intramolecular Interactions and Regulatory Mechanisms of the Scaffold Protein Tks4

The scaffold protein Tks4 is a member of the p47^phox-related organizer superfamily. It plays a key role in cell motility by being essential for the formation of podosomes and invadopodia. In addition, Tks4 is involved in the epidermal growth factor (EGF) signaling pathway, in which EGF induces the translocation of Tks4 from the cytoplasm to the plasma membrane. The evolutionarily-related protein p47^phox and Tks4 share many similarities in their N-terminal region: a phosphoinositide-binding PX domain is followed by two SH3 domains (so called “tandem SH3”) and a proline-rich region (PRR). In p47^phox, the PRR is followed by a relatively short, disordered C-terminal tail region containing multiple phosphorylation sites. These play a key role in the regulation of the protein. In Tks4, the PRR is followed by a third and a fourth SH3 domain connected by a long (~420 residues) unstructured region. In p47^phox, the tandem SH3 domain binds the PRR while the first SH3 domain interacts with the PX domain, thereby preventing its binding to the membrane. Based on the conserved structural features of p47^phox and Tks4 and the fact that an intramolecular interaction between the third SH3 and the PX domains of Tks4 has already been reported, we hypothesized that Tks4 is similarly regulated by autoinhibition. In this study, we showed, via fluorescence-based titrations, MST, ITC, and SAXS measurements, that the tandem SH3 domain of Tks4 binds the PRR and that the PX domain interacts with the third SH3 domain. We also investigated a phosphomimicking Thr-to-Glu point mutation in the PRR as a possible regulator of intramolecular interactions. Phosphatidylinositol-3-phosphate (PtdIns(3)P) was identified as the main binding partner of the PX domain via lipid-binding assays. In truncated Tks4 fragments, the presence of the tandem SH3, together with the PRR, reduced PtdIns(3)P binding, while the presence of the third SH3 domain led to complete inhibition.